Reciprocal changes in prefrontal and limbic dopamine responsiveness to aversive and rewarding stimuli after chronic mild stress: Implications for thepsychobiology of depression

Background: Chronic mild stress (CMS) has been reported to induce behaviora l abnormalities that model human depression. To investigate the role in dep ression of phasic dopamine transmission in cortical and limbic areas, we st udied the effect of CMS on the responsiveness of dopamine (DA) transmission to aversive and rewarding stimuli in rats by microdialysis of the nucleus accumbens (NAc) shell and of the medial prefrontal cortex (PFCX). Methods: Rats were subjected for 30 days to CMS and administered two trials of tail pinch as aversive stimulus and two feeding sessions of a highly pa latable food as rewarding stimulus. Concentric microdialysis probes were im planted in the NAc shell and in the medial PFCX. Results: In unstressed rats, DA decreased in the NAc and increased in the P FCX on the first tail-pinch trial; on the 1(st) feeding trial DA increased in the NAc and to a larger extent in the PFCX. In the second tail-pinch tri al or feeding trial, these responses were maintained in the PFCX but underw ent habituation in the NAc. CMS did not affect basal dialysate DA in the NA c or in the PFCX bur infleunced the responsiveness of DA transmission to ra il pinches and to feeding in a reciprocal manner. Thus, in the tail-pinch t rial, CMS reversed the inhibitory response of NAc DA transmission into a st imulatory one and potentiated the stimulatory response in the PFCX. By cont rast, in the feeding trial, CMS blunted the stimulatory response of DA tran smission in the NAc in the first trial and in the PFCX in the second trial. Conclusions: CMS reciprocally affected DA responsiveness to motivational st imuli, facilitating or inducing a stimulatory DA response to aversive stimu li but blunting stimulatory responses to rewarding stimuli. Given the postu lated role of phasic DA responsiveness in the NAc shell for learning and of DA transmission in the PFCX for expression of motivation, we hypothesize t hat depression is the result of defective learning and expression of motiva tion. aversive and appetitive motivation. Biol Psychiatry 1999;46:1624-1633 (C) 1999 Society of Biological Psychiatry.